Elevated pretreatment lactate dehydrogenase and albumin-to-alkaline phosphatase ratio predict poor prognosis and early treatment discontinuation in head and neck cancer patients with preexistent diabetes mellitus.

Increased serum lactate dehydrogenase (LDH) activity is considered as a marker of cellular necrosis and serves as a metabolomic diagnostic marker in several types of cancer including head and neck squamous cell carcinoma (HNSCC). LDH, an enzyme involved in the glycolytic cycle, is correlated not only with the activation of oncogenes such as HIF-α and Myc, but also with effects such as tumor proliferation and metastasis. Serum alkaline phosphatase (ALP) is a marker of cell differentiation and tumor induction. Albumin-to-alkaline phosphatase ratio (AAPR) could be an advantageous biomarker due to its easily accessible dynamics and cost-effectiveness. Elevated values of AAPR could be associated with longer overall survival (OS) in cases with solid tumors. Diabetes mellitus (DM) could influence the outcome of patients with HNSCC by contributing to insulin resistance and chronic inflammation, and by being involved in various aspects of carcinogenesis, disease progression and metastasis. However, the use of antihyperglycemic medications (metformin) can have beneficial effects by inhibiting tumor metabolic pathways. The biomarker role of LDH and AAPR in HNSCC patients with DM has been less evaluated. The purpose of the study was to assess the prognostic value of pretreatment serum lactate dehydrogenase (LDH) and albumin-to-alkaline phosphatase ratio (AAPR) in predicting the duration of non-surgical oncological treatment and glycemic control in cases of head and neck cancers patients with DM, including cases selected from the database of the oncology clinic and oncology outpatient clinic of the Craiova County Hospital. Both LDH and AAPR can be used as pre-treatment biomarkers predictive of treatment response, or prognostic tools included in complex multi-parametric models in HNC associated with DM. However, given the impact of short-term glycemic control on the LDH level, it is necessary to evaluate these biomarkers after assessing and controlling for DM, and with the recommended cut-off value set around 0.5. Due to the limited number of cases, it is necessary to validate the results in multicentric trials with a larger number of patients (Tab. 5, Ref. 50). Keywords: diabetes mellitus, HNC, LDH, AAPR, biomarkers, predictive, head and neck cancers, lactate dehydrogenase, albumin-to-alkaline phosphatase ratio.

Immunotherapy and radiotherapy - a future partnership Focus on radiation induced lymphopenia (RIL) implications.

The hematological toxicity associated with radiotherapy is represented by neutropenia, anemia, thrombocytopenia, being associated with the increased risk of infection with opportunists, with fatigue and intolerance to effort, but also with the increased risk of bleeding. In the context of the preclinical and clinical results that mention the synergistic effect of the immunotherapy-radiotherapy association, radiation-induced lymphopenia (RIL) becomes an immunosuppression factor, a factor that would tip the fragile antitumor immunopotentiation-immunosuppression balance in favor of the immunosuppressive effect. Both the number of lymphocytes and the neutrophil/lymphocyte ratio (NLR) are prognostic and predictive biomarkers, providing information on the immune status of the host and on a possible response of the tumor to immunotherapy. Modern radiation techniques can increase the risk of lymphopenia by irradiating large volumes of tissue with low doses of radiation. In this context, a redefinition of the dose-volume constraints and the definition of bone marrow, lymphoid organs and lymph nodes not involved in tumors as organs at risk (OARs) is strictly necessary in the case of using irradiation through intensity-modulated radiation therapy (IMRT) techniques or volumetric modulated arc therapy (VMAT) for solid tumors that benefit from immune checkpoint inhibitor (ICI) therapy (Ref. 22). Text in PDF www.elis.sk Keywords: lymphopenia, immunotherapy, radiotherapy, toxicity, spleen, nodes irradiation.

Radiobiological approach to treatment gaps in locally advanced head and neck cancers radical radiotherapy arising from the COVID-19 pandemic.

Gaps of radiotherapy treatment are one of the factors recognized as unfavorable in terms of tumor control and disease prognosis. All strategies for compensating the negative effect of radiotherapy treatment gaps are based on radiobiological models. Using the modified square linear formalism (Dale`s equation) it is possible to calculate the additional dose in order to compensate the accelerated tumor repopulation effect. SARS-CoV-2 infection is an important factor that can lead to an interruption of irradiation for medium and long- term intervals. We aim to present the radiobiological data underlying the recalculation of radiotherapy treatment and exemplification for different clinical scenarios in the case of head and neck cancers (Ref. 17). Keywords: adiobiology, treatment gaps, locally advanced head and neck cancers, radical radiotherapy, COVID-19 pandemic.

Synergies Radiotherapy-Immunotherapy in Head and Neck Cancers. A New Concept for Radiotherapy Target Volumes-"Immunological Dose Painting".

The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy-immunotherapy (RT-IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system through already known mechanisms, it is necessary to identify biomarkers that direct the "nonresponders" of immunotherapy towards a synergistic RT-IT stimulation strategy. Stimulation of the immune system by irradiation can convert "nonresponder" to "responder". With the development of modern techniques, re-irradiation is becoming an increasingly common option for patients who have previously been treated with higher doses of radiation. In this context, radiotherapy in combination with immunotherapy, both in the advanced local stage and in recurrent/metastatic of HNC radiotherapy, could evolve from the "first level" of knowledge (i.e., ballistic precision, dose conformity and homogeneity) to "level two" of "biological dose painting" (in which the concept of tumor heterogeneity and radio-resistance supports the need for doses escalation based on biological criteria), and finally to the "third level" ofthe new concept of "immunological dose painting". The peculiarity of this concept is that the radiotherapy target volumes and tumoricidal dose can be completely reevaluated, taking into account the immune-modulatory effect of irradiation. In this case, the tumor target volume can include even the tumor microenvironment or a partial volume of the primary tumor or metastasis, not all the gross and microscopic disease. Tumoricidal biologically equivalent dose (BED) may be completely different from the currently estimated values, radiotherapy treating the tumor in this case indirectly by boosting the immune response. Thus, the clinical target volume (CTV) can be replaced with a new immunological-clinical target volume (ICTV) for patients who benefit from the RT-IT association (Image 1).

Flaxseed prevents leukocyte and platelet adhesion to endothelial cells in experimental atherosclerosis by reducing sVCAM-1 and vWF.

We studied the possible effect of flaxseed to prevent leukocytes and platelets adhesion to endothelial cells and to reduce soluble adhesion molecules (sVCAM-1) and endothelial integrity markers (vWF) in ovariectomized rats fed a high-fat diet. Forty-two female Wistar rats were either sham-operated or ovariectomized and randomly assigned for 36 weeks to three different diets: (1) low-fat diet (8% energy as fat); (2) high-fat diet (40% energy as fat, lard based, lard group); (3) high-fat diet enriched with ground flaxseed 15 g/100 g of food (40% energy as fat, lard + flaxseed group). The ovariectomized rats fed with lard + flaxseeds had significantly lower serum concentrations of sVCAM and vWF, reduced platelet adhesiveness, and lower extent of platelet and leukocyte adherence to endothelium in the histological evaluation of the aorta as compared to Ovx + lard group. In our study, high dose of ground flaxseed incorporated to lard-based diet prevented the progression of atherosclerotic lesions in estrogen deficiency rats by decreasing platelet and endothelium reactivity. Assessment of platelet adhesion, serum soluble adhesion molecule sVCAM, and endothelium integrity molecule vWF could be useful to detect the risk for atherosclerotic lesions in estrogen deficiency states and to estimate the effect of flaxseed supplementation.

Active Immune Phenotype in Head and Neck Cancer: Reevaluating the Iso-Effect Fractionation Based on the Linear Quadratic (LQ) Model-A Narrative Review.

Altered fractionation concepts and especially moderate hypo-fractionation are evaluated as alternatives to standard treatment for head and neck squamous cell carcinoma (HNSCC), associated with or not concurrent with or sequential to chemotherapy. The calculation of the iso-equivalent dose regimens has as its starting point the linear quadratic (LQ) formalism traditionally based on the "4Rs" of radiobiology. The higher rates of therapeutic failure after radiotherapy of HNSCC are associated with the heterogeneity of radio-sensibility. The identification of genetic signatures and radio-resistance scores aims to improve the therapeutic ratio of radiotherapy and to conceptualize personalized fractionation schemes. The new data regarding the involvement of the sixth "R" of radiobiology in HNSCC, especially for the HPV-driven subtype, but also for the "immune active" minority of HPV-negative HNSCCs, bring to the fore a multifactorial variation of the α/ß ratio. The involvement of the antitumor immune response and the dose/fractionation/volume factors as well as the therapeutic sequence in the case of new multimodal treatments including immune checkpoint inhibitors (ICIs) could be included as an additional term in the quadratic linear formalism especially for hypo-fractionation regimens. This term should take into account the dual immunomodulatory effect (immunosuppressant and stimulator of antitumor immunity) of radiotherapy, which varies from case to case and can bring benefit or a detrimental effect.

Image Guided Radiotherapy (IGRT) and Delta (Δ) Radiomics-An Urgent Alliance for the Front Line of the War against Head and Neck Cancers.

The identification of a biomarker that is response predictive could offer a solution for the stratification of the treatment of head and neck cancers (HNC) in the context of high recurrence rates, especially those associated with loco-regional failure. Delta (Δ) radiomics, a concept based on the variation of parameters extracted from medical imaging using artificial intelligence (AI) algorithms, demonstrates its potential as a predictive biomarker of treatment response in HNC. The concept of image-guided radiotherapy (IGRT), including computer tomography simulation (CT) and position control imaging with cone-beam-computed tomography (CBCT), now offers new perspectives for radiomics applied in radiotherapy. The use of Δ features of texture, shape, and size, both from the primary tumor and from the tumor-involved lymph nodes, demonstrates the best predictive accuracy. If, in the case of treatment response, promising Δ radiomics results could be obtained, even after 24 h from the start of treatment, for radiation-induced xerostomia, the evaluation of Δ radiomics in the middle of treatment could be recommended. The fused models (clinical and Δ radiomics) seem to offer benefits, both in comparison to the clinical model and to the radiomic model. The selection of patients who benefit from induction chemotherapy is underestimated in Δ radiomic studies and may be an unexplored territory with major potential. The advantage offered by "in house" simulation CT and CBCT favors the rapid implementation of Δ radiomics studies in radiotherapy departments. Positron emission tomography (PET)-CT Δ radiomics could guide the new concepts of dose escalation on radio-resistant sub-volumes based on radiobiological criteria, but also guide the "next level" of HNC adaptive radiotherapy (ART).

Simultaneous Integrated Boost (SIB) vs. Sequential Boost in Head and Neck Cancer (HNC) Radiotherapy: A Radiomics-Based Decision Proof of Concept.

Artificial intelligence (AI) and in particular radiomics has opened new horizons by extracting data from medical imaging that could be used not only to improve diagnostic accuracy, but also to be included in predictive models contributing to treatment stratification of cancer. Head and neck cancers (HNC) are associated with higher recurrence rates, especially in advanced stages of disease. It is considered that approximately 50% of cases will evolve with loco-regional recurrence, even if they will benefit from a current standard treatment consisting of definitive chemo-radiotherapy. Radiotherapy, the cornerstone treatment in locally advanced HNC, could be delivered either by the simultaneous integrated boost (SIB) technique or by the sequential boost technique, the decision often being a subjective one. The principles of radiobiology could be the basis of an optimal decision between the two methods of radiation dose delivery, but the heterogeneity of HNC radio-sensitivity makes this approach difficult. Radiomics has demonstrated the ability to non-invasively predict radio-sensitivity and the risk of relapse in HNC. Tumor heterogeneity evaluated with radiomics, the inclusion of coarseness, entropy and other first order features extracted from gross tumor volume (GTV) in multivariate models could identify pre-treatment cases that will benefit from one of the approaches (SIB or sequential boost radio-chemotherapy) considered the current standard of care for locally advanced HNC. Computer tomography (CT) simulation and daily cone beam CT (CBCT) could be chosen as imaging source for radiomic analysis.

The Prognostic Value of Platelet-Lymphocyte Ratio, Neutrophil-Lymphocyte Ratio, and Monocyte-Lymphocyte Ratio in Head and Neck Squamous Cell Carcinoma (HNSCC)-A Retrospective Single Center Study and a Literature Review.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and pallets-to-lymphocyte ratio (PLR) are currently validated as cheap and accessible biomarkers in different types of solid tumors, including head and neck cancers (HNC). THE PURPOSE OF THE STUDY: To evaluate the possible purposes and biomarker value of NLR, PLR, and MLR recorded pre-treatment (radiotherapy/chemotherapy) in HNC. MATERIALS AND METHODS: From 190 patients with HNC included in the oncology records in the oncology outpatient clinic of the Craiova County Emergency Hospital (from January 2002 to December 2022), 39 cases met the inclusion criteria (squamous cell carcinoma and the possibility to calculate the pre-treatment (chemotherapy/radiotherapy) value of NLR, PLR, and MLR. Overall survival (OS) values were correlated with NLR, PLR, and MLR. RESULTS: The median values for NLR, PLR, and MLR were 6.15 (1.24-69), 200.79 (61.3-1775.0), and 0.53 (0.12-5.5), respectively. In the study, the mean values for NLR, PLR, and MLR of 2.88, 142.97, and 0.36, respectively, were obtained. The median OS in the study group was 11 months (1-120). Although a negative Pearson's correlation was present, the relationship between the variables was only weak, with values of R = 0.07, p = 0.67, R = 0.02, p = 0.31, and R = 0.07, p = 0.62 being related to NLR, PLR, and MLR, respectively, in correlation with OS. The median values of NLR, PLR, and MLR were calculated (1.53, 90.32, and 0.18, respectively) for the HNC cases with pre-treatment values of NLR < 2 and for the HNC cases with NLR values ≥ 6 (23.5, 232.78, and 0.79, respectively). The median OS for cases with NLR < 2 and NLR ≥ 6 were 17.4 and 13 months, respectively. CONCLUSIONS: The comparative analysis of the data highlights a benefit to OS for cases low values of NLR. The role of not only borderline NLR values (between 2 and 6) as a prognostic marker in HNSCC but also the inclusion of PLR and MLR in a prognostic score must also be defined in the future. Prospective studies with more uniformly selected inclusion criteria could demonstrate the value of pre-treatment NLR, PLR, and MLR for treatment stratification through the intensification or de-escalation of non-surgical curative treatment in HNSCC.

Immunotherapy with PD-1 Inhibitor Nivolumab in Recurrent/Metastatic Platinum Refractory Head and Neck Cancers-Early Experiences from Romania and Literature Review.

Prognosis in recurrent/metastatic head and neck squamous-cell carcinoma (HNSCC) refractory to platinum-based chemotherapy is poor, making therapy optimization a priority. Anti-programmed cell death protein 1 (anti-PD-1) monoclonal antibody Nivolumab was approved in such cases. We present the early experience with Nivolumab immunotherapy at three cancer clinics from south and northeast Romania, aiming to describe the main characteristics and outcomes relative to literature reports, and to suggest patient selection criteria. Diagnostic, clinical, biological, therapeutic, and outcomes-related data from January 2020 until March 2023 were analyzed retrospectively. Eighteen patients with platinum refractory HNSCC (85.7% men, median age 58.9) were administered Nivolumab for 1-14 months (median 5.6 months) in addition to other treatments (surgery, radiotherapy, chemotherapy), and monitored for up to 25 months. Median neutrophil-to-lymphocyte ratio (NLR) ranged from 2.72 initially to 6.01 during treatment. Overall survival (OS) was 16 months, and patients who died early had the sharpest NLR increases (13.07/month). There were no severe immune-related adverse events. Lower NLR values and combined intensive chemotherapy, radiotherapy, and immunotherapy were related to better outcomes. To our knowledge, we also report the first two cases of second primary malignancy (SPM) in the head and neck region treated with Nivolumab in Romania (for which the sequential administration of radiotherapy and immunotherapy seems better). The work of other Romanian authors on the role of HPV status in HNC is also discussed. Multi-center trials are needed in order to investigate and confirm these observations.

Head and Neck Low Grade Chondrosarcoma-A Rare Entity.

Chondrosarcoma represents approximately 0.1% of all neoplasms of the head and neck and is considered a rare disease with a relatively good prognosis. The 5-year overall survival (OS) rate is estimated at 70-80%, being considered a disease with a low growth rate. Approximately 13% of all cases of chondrosarcoma are located in the region of the head and neck. We present the case of a 30-year-old patient without a medical history who reported dysphagia, swallowing difficulty, neck mass sensation and dysphonia that started insidiously after an upper respiratory tract infection. Subsequently, the patient was diagnosed with a low-grade glosso-epiglottic region chondrosarcoma and was multimodally treated with surgery followed by chemotherapy and radiotherapy. The radiation treatment was delivered with a Rokus M40 former Soviet Union cobalt machine without any image guidance capabilities. The inability to obtain resection margin information justified an aggressive adjuvant treatment with chemotherapy and radiotherapy. The early loss from the oncological record without recurrence of the disease could be associated in this case with the consequence of a major complication, of which we could assume an aspiration pneumonia secondary to a dysphagia associated with an aggressive multidisciplinary treatment. Large tumor size and positive resection margins (R1 resection) are risk factors that support an intensive adjuvant approach in order to reduce the risk of recurrence, but the low grade of tumor associated with a lower risk of recurrence as well as the adverse events (AE) of adjuvant radiotherapy and chemotherapy justify a more reserved therapeutic approach. Taking into account the longer life expectancy of these patients, it is recommended to use a more conformal irradiation technique in order to reduce doses to radiosensitive structures as well as to omit elective neck irradiation, taking into account the lower risk of lymph node involvement. The lack of guidelines, which include very rare tumors including low grade chondrosarcoma of the head and neck, makes a unified approach difficult, but the data presented in case reports could contribute to choosing the regimen that offers the best therapeutic ratio.

Hypofractionated Whole-Breast Irradiation Focus on Coronary Arteries and Cardiac Toxicity-A Narrative Review.

Breast cancer is the most common cancer among women worldwide, which is often treated with radiotherapy. Whole breast irradiation (WBI) is one of the most common types of irradiation. Hypo-fractionated WBI (HF-WBI) reduces the treatment time from 5 to 3 weeks. Recent radiobiological and clinical evidence recommended the use of HF-WBI regardless of the age or stage of disease, and it is proven that hypo-fractionation is non-inferior to conventional fractionation regimen irradiation. However, some studies report an increased incidence of heart-related deaths in the case of breast irradiation by hypo-fractionation, especially in patients with pre-existing cardiac risk factors at the time of treatment. Due to the new technical possibilities of radiotherapy techniques, HF-WBI can reduce the risk of cardiac toxicity by controlling the doses received both by the heart and by the anatomical structures of the heart. The radiobiological "double trouble", in particular "treble trouble", for hypo-fractionated regimen scan be avoided by improving the methods of heart sparing based on image-guided irradiation (IGRT) and by using respiration control techniques so that late cardiac toxicity is expected to be limited. However, long-term follow-up of patients treated with HF-WBI with modern radiotherapy techniques is necessary considering the progress of systemic therapy, which is associated with long-term survival, and also the cardiac toxicity of new oncological treatments. The still unknown effects of small doses spread in large volumes on lung tissue may increase the risk of second malignancy, but they can also be indirectly involved in the later development of a heart disease. It is also necessary to develop multivariable radiobiological models that include histological, molecular, clinical, and therapeutic parameters to identify risk groups and dosimetric tolerance in order to limit the incidence of late cardiac events. MR-LINAC will be able to offer a new standard for reducing cardiac toxicity in the future, especially in neoadjuvant settings for small tumors.

Micro-RNAs, the Cornerstones of the Future of Radiobiology in Head and Neck Cancers?

Even though it is only the 6th most common malignancy at the modal level, head and neck cancers are distinguished by a considerable treatment failure rate, especially by locoregional recurrences, the intrinsic tumor radioresistance being one of the causes of this phenomenon. The efforts of radiobiological research of these cancers are oriented towards the identification of biomarkers associated with radioresistance and radiosensitivity in order to modulate the treatment so that the therapeutic benefit is maximum. Micro-RNAs (miRNAs, miRs), small single-stranded non-coding RNA molecules are currently being extensively evaluated as potential biomarkers in numerous diseases, including cancer. The evaluation of the potential of miRNAs to modulate or predict radiosensitivity or radioresistance, to anticipate the risk of recurrence and metastasis, and to differentiate different tumor subtypes is based on multiple mechanisms by which mRNAs control proliferation and apoptosis and interact with cell cycle phases or act as oncogenes with the potential to influence invasion promotion or tumor suppression. A refinement of radiosensitivity based on miRNAs with clinical and radiobiological application in head and neck cancers can lead to a personalization of radiotherapy. Thus, a miRNA signature can anticipate the risk of toxicity associated with chemoradiation, the possibility of obtaining locoregional control after treatment, and the recurrence and distant metastasis risk. The potential of miRNAs as an intrinsic predictor of sensitivity to chemotherapy may also guide the therapeutic decision toward choosing an escalation or de-escalation of concurrent or sequential systemic treatment. The choice of the irradiated dose, the fractional dose, the fractionation scheme, and the refining of the dose-volume constraints depending on the radiosensitivity of each tissue type estimated on a case-by-case basis by miRNAs profile are possible concepts for the future radiotherapy and radiobiology of head and neck cancers.

Education in Radiation Oncology-Current Challenges and Difficulties.

The evolution and development of radiotherapy in the last two decades has meant that postgraduate medical training has not kept up with this rapid progress both in terms of multidisciplinary clinical approaches and especially in terms of technological advances. Education in radiation oncology is a major priority in the context of the rapid development of radiotherapy, including advanced knowledge of radiobiology, radiation physics and clinical oncology, anatomy, tumor biology and advanced medical imaging. In this context, the lack of training in radiation oncology in the curricula of medical faculties may have detrimental consequences for the training of residents in radiotherapy but also in their choice of specialty after completing their university studies. There is a clear gap between resident physicians' actual and required knowledge of radiotherapy, and this requires urgent remediation. In the context of technical advances in imaging-guided radiotherapy (IGRT) and new radiobiology data, a balanced approach divided equally between general oncology, clinical radiation oncology, radiation oncology technology, medical physics and radiobiology, anatomy and multimodal imaging, including mentorship could bring educational and career choice benefits for students of radiation oncology.

Capecitabine-A "Permanent Mission" in Head and Neck Cancers "War Council"?

Capecitabine, an oral pro-drug that is metabolized to 5-FU, has been used in clinical practice for more than 20 years, being part of the therapeutic standard for digestive and breast cancers. The use of capecitabine has been evaluated in many trials including cases diagnosed in recurrent or metastatic settings. Induction regimens or a combination with radiation therapy were evaluated in head and neck cancers, but 5-FU still remained the fluoropyrimidine used as a part of the current therapeutic standard. Quantifications of levels or ratios for enzymes are involved in the capecitabine metabolism to 5-FU but are also involved in its conversion and elimination that may lead to discontinuation, dose reduction or escalation of treatment in order to obtain the best therapeutic ratio. These strategies based on biomarkers may be relevant in the context of the implementation of precision oncology. In particular for head and neck cancers, the identification of biomarkers to select possible cases of severe toxicity requiring discontinuation of treatment, including "multi-omics" approaches, evaluate not only serological biomarkers, but also miRNAs, imaging and radiomics which will ensure capecitabine a role in both induction and concomitant or even adjuvant and palliative settings. An approach including routine testing of dihydropyrimidine dehydrogenase (DPD) or even the thymidine phosphorylase (TP)/DPD ratio and the inclusion of miRNAs, imaging and radiomics parameters in multi-omics models will help implement "precision chemotherapy" in HNC, a concept supported by the importance of avoiding interruptions or treatment delays in this type of cancer. The chemosensitivity and prognostic features of HPV-OPC cancers open new horizons for the use of capecitabine in heavily pretreated metastatic cases. Vorinostat and lapatinib are agents that can be associated with capecitabine in future clinical trials to increase the therapeutic ratio.

p53 Modulates Radiosensitivity in Head and Neck Cancers-From Classic to Future Horizons.

p53, initially considered a tumor suppressor, has been the subject of research related to cancer treatment resistance in the last 30 years. The unfavorable response to multimodal therapy and the higher recurrence rate, despite an aggressive approach, make HNSCC a research topic of interest for improving therapeutic outcomes, even if it is only the sixth most common malignancy worldwide. New advances in molecular biology and genetics include the involvement of miRNA in the control of the p53 pathway, the understanding of mechanisms such as gain/loss of function, and the development of different methods to restore p53 function, especially for HPV-negative cases. The different ratio between mutant p53 status in the primary tumor and distant metastasis originating HNSCC may serve to select the best therapeutic target for activating an abscopal effect by radiotherapy as a "booster" of the immune system. P53 may also be a key player in choosing radiotherapy fractionation regimens. Targeting any pathway involving p53, including tumor metabolism, in particular the Warburg effect, could modulate the radiosensitivity and chemo-sensitivity of head and neck cancers.

New horizons in modulating the radio-sensitivity of head and neck cancer - 100 years after Warburg' effect discovery.

Tumor radiation resistance along with chemotherapy resistance is one of the main causes of therapeutic failure of radiotherapy-treated head and neck cancers. 100 years after the discovery of the Warburg effect, a process specific to malignant cells to metabolize glucose especially anaerobically even under normoxia condition, its modulation has become a viable therapeutic target for improving the results of cancer therapies. Improving the radio-sensitivity of head and neck tumors by reversing the Warburg effect can increase the rate of local control and reduce the toxicity associated with irradiation. P53 status can be used as a biomarker in the choice of a single agent strategy (cell respiration inhibition with Metformin) or double inhibition, both of respiration and glycolysis. Targeting of enzymes involved in the Warburg effect, such as Hexokinase-II, are strategies with potential to be applied in clinical practice with radio-sensitizing effect for head and neck squamous cell carcinoma. Even if anti-Warburg therapies tested in clinical trials have been associated with either toxic deaths or a minor clinical benefit, the identification of both potential radio-sensitivity biomarkers and methods of reversing the Warburg effect will play an important role in the radiobiology of head and neck cancers.

Immunotherapy and Radiotherapy as an Antitumoral Long-Range Weapon-A Partnership with Unsolved Challenges: Dose, Fractionation, Volumes, Therapeutic Sequence.

Immunotherapy, the modern oncological treatment with immune checkpoint inhibitors (ICIs), has been part of the clinical practice for malignant melanoma for more than a decade. Anti-cytotoxic T-lymphocyte antigen 4 (CTLA4), anti-programmed cell death Protein 1 (PD-1), or anti programmed death-ligand 1 (PD-L1) agents are currently part of the therapeutic arsenal of metastatic or relapsed disease in numerous cancers; more recently, they have also been evaluated and validated as consolidation therapy in the advanced local stage. The combination with radiotherapy, a treatment historically considered loco-regional, changes the paradigm, offering-via synergistic effects-the potential to increase immune-mediated tumor destruction. However, the fragile balance between the tumoricidal effects through immune mechanisms and the immunosuppression induced by radiotherapy means that, in the absence of ICI, the immune-mediated potentiation effect of radiotherapy at a distance from the site of administration is rare. Through analysis of the preclinical and clinical data, especially the evidence from the PACIFIC clinical trial, we can consider that hypofractionated irradiation and reduction of the irradiated volume, in order to protect the immune-infiltrated tumor microenvironment, performed concurrently with the immunotherapy or a maximum of 2 weeks before the start of ICI treatment, could bring maximum benefits. In addition, avoiding radiation-induced lymphopenia (RILD) by protecting some anatomical lymphoid structures or large blood vessels, as well as the use of irradiation of partial tumor volumes, even in plurimetastatic disease, for the conversion of a "cold" immunological tumor into a "hot" immunological tumor are modern concepts of radiotherapy in the era of immunotherapy. Low-dose radiotherapy could also be proposed in plurimetastatic cases, the effect being different (modeling of the TME) from that of high doses per fraction irradiation (cell death with release of antigens that facilitates immune-mediated cell death).

Radiomics in Triple Negative Breast Cancer: New Horizons in an Aggressive Subtype of the Disease.

In the last decade, the analysis of the medical images has evolved significantly, applications and tools capable to extract quantitative characteristics of the images beyond the discrimination capacity of the investigator's eye being developed. The applications of this new research field, called radiomics, presented an exponential growth with direct implications in the diagnosis and prediction of response to therapy. Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with a severe prognosis, despite the aggressive multimodal treatments applied according to the guidelines. Radiomics has already proven the ability to differentiate TNBC from fibroadenoma. Radiomics features extracted from digital mammography may also distinguish between TNBC and non-TNBC. Recent research has identified three distinct subtypes of TNBC using IRM breast images voxel-level radiomics features (size/shape related features, texture features, sharpness). The correlation of these TNBC subtypes with the clinical response to neoadjuvant therapy may lead to the identification of biomarkers in order to guide the clinical decision. Furthermore, the variation of some radiomics features in the neoadjuvant settings provides a tool for the rapid evaluation of treatment efficacy. The association of radiomics features with already identified biomarkers can generate complex predictive and prognostic models. Standardization of image acquisition and also of radiomics feature extraction is required to validate this method in clinical practice.

An Underestimated Toxicity Radiation-Induced Hypothyroidism in Patients Multimodally Treated for Breast Cancer.

Radiation therapy is part of the therapeutic arsenal for breast cancer, whether it is adjuvant treatment after lumpectomy or radical mastectomy, or it is used as a palliative option in the case of metastatic or recurrent disease. Significant advances in diagnostic and therapeutic stratification of breast cancers have significantly prolonged survival, even in the metastatic stage. Exposure of patients during the course of the disease in a multidisciplinary therapeutic approach including chemotherapy, hormone therapy, targeted anti-HER therapies or CDK4/6 inhibitors had led to improved survival but with the price of additional toxicity. Among them, hypothyroidism is a well-known consequence of external radiation therapy, especially in the case of cervical region irradiation, including supraclavicular and infra-clavicular nodal levels. In this situation, the thyroid gland is considered as an organ at risk (OAR) and receives a significant dose of radiation. Subclinical hypothyroidism is a common endocrine disorder characterized by elevated TSH levels with normal levels of FT4 (free T4) and FT3 (free T3), and as a late effect, primary hypothyroidism is one of the late effects that significantly affects the quality of life for patients with breast cancer receiving multimodal treatment. Hypothyroidism has a significant impact on quality of life, most often occurring as late clinical toxicity, secondary to thyroid irradiation at doses between 30 and 70 Gy. Dose-volume parameters of irradiation, gland function at the beginning of the treatment and associated systemic therapies may be factors that alter thyroid radio-sensitivity and affect thyroid gland tolerance. In the case of head and neck tumor pathology, in which doses of >50 Gy are routinely used, the thyroid gland is generally considered as an OAR, the rate of radio-induced hypothyroidism being estimated at rates of between 20% and 52%. For breast cancer, the thyroid is often neglected in terms of dosimetry protection, the rate of late dysfunction being 6-21%.